DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status Summary
Claims 49- 62 are pending.
Claims 49- 62 are examined on the merits.
Claims 49, 51- 54, and 59 are objected.
Claims 50, 55- 57, 60, and 62 are rejected.
Claim 49 and 58 is allowed.
Applicant’s election without traverse of Species Group A, "a sense strand," SEQ ID NO: 71, with nucleotide modification pattern according to SEQ ID NO: 460 and Species Group B, "an antisense strand," SEQ ID NO: 16, with nucleotide modification pattern according to SEQ ID NO: 447 in the reply filed on 2026 June 10 is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 60 and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Breadth of the Claims
Claims 60 and 62 broadly claim a method of downregulating the expression of AGT, or treating any disease associated with aberrant AGT expression or any disease where AGT plays a role. The methods of claims 60 and 62 further include means to downregulate AGT or treat AGT associated disease by administering the dsRNA oligonucleotide of claim 58 and dsRNA oligonucleotide of claim 49 respectively. The oligonucleotides of claims 58 and 49 effectively act as drugs. The AGT suppression via dsRNA mediated RNAi somehow leads to the subject being treated of whatever disorder ails them due to their aberrant AGT expression.
Support Provided by Specification
The specification provides no data directed toward testing, preventing or treating any disease or disorder.
The specifications provide data in Fig. 2, Fig. 3, and Fig 5 indicating their oligonucleotide reduces AGT mRNA expression in cells, mouse liver and Macaca fascicularis liver respectively.
The instant specification further describes hypertension and other diseases and disorders due to misregulation of AGT mRNA, “Hypertension a major risk factor for various diseases, disorders and conditions such as, shortened life expectancy, chronic kidney disease, stroke, myocardial infarction, heart failure, aneurysms (e.g. aortic aneurysm), peripheral artery disease, heart damage (e.g., heart enlargement or hypertrophy) and other cardiovascular related diseases, disorders and/or conditions.” [004].
State of Prior Art and Determination of Possession of Invention
This examiner was unable to find any evidence in the prior art of any GalNAc−siRNA conjugates that prevents a disease or disorder associated with aberrant AGT.”
Kulkarni (Kulkarni et al. Nat Nanotechnol. 2021 Jun;16(6):630-643.) teaches the current potential advantages of RNAi based therapies as well as some challenges “nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing” (Abstract); and “Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity” (Abstract); and “employing nucleic acids as therapeutics is challenging because they are susceptible to degradation by nucleases, contribute to immune activation and have unfavourable physicochemical characteristics that prevent facile transmission into cells” (page 630, 1st column, 2nd paragraph). Kulkarni further describes several diseases approved for treatment via nucleic acid therapies “Several ex vivo and in vivo genetic drugs have recently been approved (or are in late-stage development) for treating infections, cancer, muscular and retinal dystrophies, and other inherited disorders” (page 630, 1st column, 3rd paragraph). Kulkarni even identifies the technology described in the instant invention “The vast majority of nucleic acid therapeutics that are either already approved or currently in late-stage clinical evaluation rely on four platform technologies: chemically modified antisense oligonucleotides (ASOs), N-acetylgalactosamine (GalNAc) ligand-modified short interfering RNA (siRNA) conjugates…”(page 630, 2nd column, 2nd paragraph). Crooke (Crooke et al. Cell Metab. 2018 Apr 3;27(4):714-739) identifies RNAi based therapies targeting AGT to treat hypertension (clinical trial ID NCT03101878, completed 2018 Aug 1, see Table 1, page 723 ).
However, despite the instant claims’ seemingly similarity to the current state of the art, there are challenges and unpredictability between the state of the art and the instant claim that the specifications does not resolve, as noted below.
Wu (Wu et al. Biosci Rep. 2019 Jan 11;39(1):BSR20180201.) provides evidence that RNAi therapy as noted in the instant application is promising, but fails to provide any statement of certainty or predictability, “Profound reductions in blood pressure and improvement of kidney pathologies by AGT ASO in hypertensive rat models with kidney dysfunctions engenders confidence that AGT ASOs may have beneficial effects in addition to controlling blood pressure.” (page 7, 3rd paragraph).
Furthermore, Ayyar (Ayyar et al. J Pharmacol Exp Ther. 2021 Nov;379(2):134-146.) shows there is no means of establishing a predictive disease treatment outcome based on early stage data, “Conjugation of small interfering RNA (siRNA) to tris N-acetyl galactosamine [(GalNAc)3] can enable highly selective, potent, and durable knockdown of targeted proteins in the liver. However, potential knowledge gaps between in vitro experiments, preclinical species, and clinical scenarios remain” (Abstract). As evidenced by Ayyar, there is no predictive outcome based on the early stage data presented in the instant application. Furthermore, the disease models cited within the instant specification are vastly different with vastly different mechanisms and biological pathways, leading to further unpredictability. Referring to Ayyar, there are likely knowledge gaps between in vitro experiments, preclinical species, and clinical scenarios. For example, biochemical systems in in vitro experiments may not present a wholistic disease picture; species’ physiology varies, leading to variations in reactions; and subjects in clinical scenarios similarly have variations in reactions.
This variability is emphasized by, Lin (Lin JH. Pharmacokinetic and pharmacodynamic variability: a daunting challenge in drug therapy. Curr Drug Metab. 2007 Feb;8(2):109-36.). Regarding the “administering to the subject an effective amount of the isolated oligonucleotide [drug],” the state of the art includes multitudes of drugs. However, Lin further demonstrates the unpredictability with drug therapy, “Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others” (Abstract).
As noted above, the claim recites a broad genus of preventing and treating diseases using a dsRNA but, in light of the data presented and challenges and unpredictability in the art, the applicant fails to show a proper sampling of disease prevention and treatment that are indicative of the broad diseases claimed, such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 50 is rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more. The claim(s) recite(s) SEQ ID No 16 which is identical to angiotensinogen (AGT) gene (NCBI ascension AH002594.2 Homo sapiens angiotensinogen (AGT) gene, complete cds; 2016 June 10) (https://blast.ncbi.nlm.nih.gov/Blast.cgi). Bases 1- 22 of SEQ ID No 16 align complimentary 100% with bases 3099- 3078 of the AGT gene. Similarly, bases 1- 20 of the instant claimed SEQ ID No 71 align complimentary 100% with the same section of bases, 3080- 3099 of the aforementioned AGT gene (https://blast.ncbi.nlm.nih.gov/Blast.cgi). These two complimentary sequences as described in the claim have no features that are markedly different from native DNA and furthermore, the claimed sequences convey the same genetic information as their native DNA counterpart.
This judicial exception is not integrated into a practical application because the claim does not recite any additional elements.
Regarding steb 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim does not recite additional elements.
Therefore, the isolated oligonucleotide of the instant claim is merely an isolated natural nucleic acid duplex found in nature and therefore not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 50 and 55 is/are rejected under 35 U.S.C. 103 as being unpatentable over is Nioi (Nioi US 20240392294 A1, effectively filed 2021 Aug 4).
Regarding claim 50, Nioi discloses “RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting an angiotensinogen (AGT) gene.” [Abstract]. Nioi further discloses “Double stranded RNAi compounds of the invention may be prepared using a two-step procedure. First, the individual strands of the double stranded RNA molecule are prepared separately. Then, the component strands are annealed.” [0158]. Nioi’s RNAi preparation procedure is consistent with the instant specification’s description of “isolated” oligonucleotides [see 0101].
Nioi discloses a 23 base SEQ ID NO 2780 whose bases 1- 22 match bases 1-22 of instant SEQ ID NO 447 100%. SEQ ID NO 2780 is described in Table 5 as an “mRNA Target Sequence.”
Nioi Further discloses the 21 base oligonucleotide SEQ ID NO 1650 whose bases 1- 20 match instant SEQ ID NO 460 bases 1- 20 100%. All 20 bases of SEQ ID No 1650 are complementary to bases 1-20 of SEQ ID 2780. Nioi further teaches how to use their oligonucleotides “A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence” [0151].
It would have been obvious for a person having ordinary skill in the art (PHOSITA) to have taken the anti-AGT oligonucleotide 1650 of Nioi and combined it with the SEQ ID NO 2780, complimentary strand that matches the AGT mRNA identified and targeted by Nioi because Nioi’s teaching, of SEQ ID NO 2780, SEQ ID NO 1650, preparation of dsRNA, and suggestion of how to use their dsRNA oligonucleotides, would have led one of ordinary skill to combine Nioi’s teachings and procedures to arrive at the claimed invention. Nioi taught all of the elements of the isolated oligonucleotide. They taught the isolated oligonucleotide by showing they targeted AGT via RNAi as described above: they teach targeting a particular polynucleotide (AGT) and they teach generating and isolating a dsRNA based on the particular AGT nucleotide. Therefore, Nioi teaches the methods described above work in combination with each other as exemplified in their embodiment, “administration of the dsRNA agent to the subject causes a decrease in AGT protein accumulation in the subject” [0055]. Therefore, a PHOSITA would similarly recognize Nioi’s complimentary sequences SEQ ID Nos 2780 and 1650, would lead to the oligonucleotide of the claimed invention. .
Regarding claim 55, Nioi discloses “In one embodiment, the dsRNA agent further comprises a ligand [0030]; and In one embodiment, the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent [0031]; and In one embodiment, the ligand is an N-acetylgalactosamine (GalNAc) derivative.” [0032].
Claim(s) 56 and 57 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nioi (Nioi US 20240392294 A1, effectively filed 2021 Aug 4) as applied to claims 50 and 55 above, and further in view of Nair (Nair et al. J Am Chem Soc. 2014 Dec 10;136(49):16958-61.) as evidenced by Alfa Chemistry (Alfa Chemistry. 2026. GalNAc-Conjugated Oligonucleotides_ Precision Hepatocyte Delivery for Next-Generation siRNA & ASO Therapeutics. https://www.alfachemic.com/oligonucleotide-therapeutics/galnac-conjugated-oligonucleotides-precision-hepatocyte-delivery-for-next-generation-sirna-aso-therapeutics.html).
Regarding claim 56 and 57, Nioi teaches all of the elements of claims 50 and 55.
Nioi does not teach the limitation “the isolated oligonucleotide comprises three GalNAc Glb moieties.”
However, Nair teaches “Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo” [Abstract]. Nair further teaches the necessity of multivalency “Multivalency and the presence of Ca2+ ions are prerequisites for proper recognition and binding of the ligands to the carbohydrate recognition domain of the receptor” page 16958, 2nd column, 2nd paragraph). Furthermore, Nair teaches their trivalent GalNAc moieties “triantennary GalNAc ligands were reengineered to facilitate covalent conjugation to siRNAs” (page 16959, 1st column, 1st paragraph).
Furthermore, Nair provides additional motivation for attaching their GalNAc moiety to siRNA “improved pharmacokinetics relative to the unconjugated siRNAs” (page 16959, 1st column, 1st paragraph) and “subcutaneous delivered siRNA conjugates is desirable” (page 16958, 2nd column, 1st paragraph). Nair further teaches GalNAc design may be optimized stating “Optimal design of multivalent GalNAc-conjugated siRNAs can elicit robust RNAi-mediated gene silencing in hepatocytes in vitro and in vivo” (page 16961, 1st column, 2nd paragraph). Nair provides a GalNAc structure similar to the instant GalNAc Glb (images below, left and right respectively).
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One embodiment of Nioi’s GalNAc is shown below.
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It would be obvious for a PHOSITA to substitute Nair’s trivalent GalNAc for Nioi’s GalNAc to arrive at the instant GalNAc Glb because it is a simple substitution of one known element for another to obtain predictable results. Nair and Nioi both were in the field of GalNAc-siRNA conjugates. The difference between Nioi’s GalNAc and Nair’s GalNAc is the linker. Furthermore, the linker difference between the prior art (Nair and Nioi) and the instant claim is simply a matter of routine optimization, as cited previously and reiterated by Alfa Chemistry “Linker choice affects receptor binding, endosomal release, and the kinetics of ligand detachment; optimized linkers allow the GalNAc moiety to be cleaved or metabolized after endocytosis so that the payload can access the RNAi machinery or RNase H.” (Website). Therefore, a PHOSITA would have recognized and predicted the GalNAc of Nair would have been a successful substitute for Nioi’s GalNAc.
Allowable Subject Matter
Claim 49 and 58 are allowed.
The closest relevant prior found by this examiner is Nioi (Nioi US 20240392294 A1, effectively filed 2021 Aug 4). Nioi discloses “RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting an angiotensinogen (AGT) gene.” [Abstract]. ). Nioi discloses a 23 base SEQ ID NO 2780 whose bases 1- 22 match bases 1-22 of instant SEQ ID NO 447 100%. SEQ ID NO 2780 is described in Table 5 as an “mRNA Target Sequence.” Nioi further describes sense and antisense oligos that comprise the double stranded RNAi molecule that targets mRNA SEQ ID NO 2780. The disclosed sense and antisense oligos comprise base, backbone, and terminus modifications including 2' -O-methyl modified nucleotides, 2' -F modified nucleotides, phosphorothioate internucleotide linkages, and GalNAc moieties. However, these modifications are not identical such that SEQ ID NO 2780 has an identical structure to SEQ ID NO 447.
Furthermore, Nioi discloses 21 base oligonucleotide SEQ ID NO 2173 whose bases 1- 20 match instant SEQ ID NO 460 bases 1- 20 100%. However, the modifications (as described above) of SEQ ID NO 2173 are such that it does not have the identical structure to instant SEQ ID No 460.
Furthermore, this examiner was not able to find any record in the prior art indicating the oligonucleotide as claimed was obvious. For example, this examiner did not find any record indicating the chemical modification pattern of SEQ ID NOs 447 and 460 were known and obvious.
For these reasons, claims 49 and 58 are allowable.
Claims 51- 54, and 59 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claims 51- 54, This examiner was not able to find prior art over the recited base modifications in combination with the recited sequences. The instant SEQ ID No 16 of claim 50 shares the same primary sequence and base modification pattern as SEQ ID No 447 of claim 58 (and 49). Similarly, instant SEQ ID No 71 of claim 51 shares the same primary sequence and base modification pattern as SEQ ID No 460 of claim 58 (and 49). Likewise, the closest relevant prior art found was Nioi and these claim limitations are otherwise allowable for the same reasons stated above.
Conclusion
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/AARON DUREL WARD/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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